For individuals suffering from end-stage organ failure, organ transplantation continues to represent the primary therapeutic intervention. While standard broad-spectrum immunosuppressants prove effective in mitigating acute transplant rejection, they unfortunately fall short in managing chronic rejection and are often associated with detrimental long-term sequelae, including increased susceptibility to infections, the development of malignancies, and metabolic dysregulations. Consequently, the paramount objective in transplant immunology has shifted towards achieving donor-specific immune tolerance while simultaneously minimizing systemic immunosuppression.
Within the intricate immunological milieu of transplantation, regulatory T cells are widely recognized as pivotal regulators of immune equilibrium. Rather than operating through a singular mechanism, these Tregs orchestrate a multifaceted array of precise actions to establish a robust defense against graft rejection.
Featured in Volume 2, article number 23 of the journal Immunity & Inflammation, published on April 30, 2026, the research group led by Professor Xiao-Kang Li offers an initial synthesis of the universally applicable mechanisms by which Tregs exert their regulatory influence in solid organ transplantation. Through the elaboration of inhibitory cytokines such as IL-10 and TGF-β, the induction of apoptotic pathways in effector T cells, and the modulation of dendritic cell functionality, Tregs are instrumental in fostering sustained immune tolerance, both locally at the transplant site and throughout the entire organism. This comprehensive suite of regulatory strategies provides the foundational biological rationale for overcoming the common challenges of rejection that affect various transplanted organs, including the liver, kidney, and heart. A profound comprehension of these overarching principles constitutes the initial stride towards sophisticated immune modulation.
The subsequent critical question posed is how to enhance the controllability, targeting precision, and accessibility of Tregs for widespread clinical implementation. This review meticulously chronicles the technological advancements in Treg therapy, charting its progression from foundational research to clinical application, and highlights a significant transformation from traditional methodologies to state-of-the-art genetic engineering approaches.
The initial phase of development centered on polyclonal Tregs. Early investigations concentrated on ex vivo expansion of autologous Tregs. Although the safety profile of this method was established, it encountered limitations related to insufficient specificity and difficulties in achieving efficient expansion. The subsequent phase introduced CAR-Tregs (chimeric antigen receptor-engineered Tregs). The incorporation of CAR technology effectively equipped Tregs with a sophisticated “guidance system,” enabling them to accurately identify graft-specific antigens and exert potent localized immunosuppressive effects.
The most recent and transformative development involves the creation of “off-the-shelf” universal Treg products. The field is currently at a pivotal juncture, employing gene-editing technologies like CRISPR-Cas9 to generate hypoimmunogenic Tregs. By functionally disabling human leukocyte antigen molecules, these engineered Tregs possess the capacity to circumvent the recipient’s immune response, thereby facilitating their availability as standardized, scalable, “off-the-shelf” therapeutic agents. This progressive evolution in technology is steering transplant medicine away from highly individualized and complex surgical interventions towards a paradigm of standardized, accessible cell-based drug therapies.
“Future advancements in transplant immunology will necessitate the integration of universal technological platforms, exemplified by universal CAR-Tregs, with a profound understanding of the unique immune microenvironments characteristic of specific organs,” the authors emphasize. By amalgamating the precise targeting capabilities of CARs, the inherent convenience of off-the-shelf products, and the potent effects of synergistic immune regulation, Treg therapy is poised to emerge as a meticulously designed translational medicine strategy. Its aim is to confer durable, stable immune tolerance upon patients across the entire spectrum of solid organ transplantation, thereby ushering in a new epoch of “immunosuppression-free” transplantation.
This extensive review meticulously outlines the complete paradigm shift from passive immunosuppression to the active induction of tolerance. By interconnecting fundamental biological mechanisms, variations in organ-specific microenvironments, iterative technological refinements, and clinical translation, it furnishes both theoretical substantiation and practical avenues for enhancing long-term outcomes in solid organ transplantation. “As gene editing, cell engineering, and precision immune regulation technologies become increasingly interwoven, Treg cell therapy is set to represent a landmark breakthrough in transplant medicine, ultimately realizing the aspirational goal of minimal or zero reliance on immunosuppressants,” the authors project optimistically.
Li, S. W., et al. (2026) From immunosuppression to active tolerance induction: an evolving paradigm of regulatory T cell-based therapy in organ transplantation. Immunity & Inflammation. DOI: 10.1007/s44466-026-00037-1. https://link.springer.com/article/10.1007/s44466-026-00037-1
